2,4-diamino-substituted thieno(3,2-d)pyrimidines and salts thereof

ABSTRACT

Compounds of the formula   WHEREIN: R1 and R2, which may be identical to or different from each other, are each A. HETEROCYCLIC AMINO SELECTED FROM THE GROUP CONSISTING OF PIPERAZINO, N&#39;&#39;-benzyl-piperazino, N&#39;&#39;-lower alkyl piperazino, N&#39;&#39;-(hydroxylower alkyl)-piperazino, 1,4-diazacyclo-heptano, morpholino, thiomorpholino, 1-oxidothiomorpholino, 1,1dioxide-thiomorpholino, hexahydro-1,4-thiazepino and 1-oxidohexahydro-1,4-thioazepino, where each of these heterocycles may optionally have one or two lower alkyl substituents attached to ring carbon atoms; or B. ACYCLIC AMINO SELECTED FROM THE GROUP CONSISTING OF DI-LOWER ALKANOL-AMINO, N-(methylmercapto-ethyl)-methylamino and N(methylsulfinyl-ethyl)-methylamino; and R3 and R4, which may be identical to or different from each other, are each hydrogen, halogen, lower alkyl, phenyl or nitro, AND THEIR NON-TOXIC, PHARMACOLOGICALLY ACCEPTABLE ACID ADDITION SALTS; THE COMPOUNDS AS WELL AS THEIR SALTS ARE USEFUL AS INHIBITORS OF THROMBOCYTE AGGREGATION AND ADHESIVENESS, AND THOSE WERE R1 and/or R2 is 1-oxide-thiomorpholino are also useful as hypotensives.

Eilnited States Patent 1 Nari et a1.

[ June 10, 1975 [75] Inventors: Berthold Narr; Josef Roch; ErichMiiller; Josef Nicki, all of Biberach an der Riss, Germany [73]Assignee: Boehringer Ingelheim GmbH,

lngelheim am Rhein, Germany [22] Filed: May 3, 1972 21 Appl.No.:249,782

[30] Foreign Application Priority Data May 4, 1971 Germany 2121950 July26, 1971 Germany 2137431 Mar. 29, 1972 Germany 2215299 [52] US. Cl260/243 R; 260/243 B; 260/247.1; 260/251 A; 260/2565 R; 424/246;424/248; 424/251 [51] Int. Cl C07d 99/10 [58] Field of Search 260/2565R, 243 B, 243 R [56] References Cited UNITED STATES PATENTS 3,259,623'7/1966 Kober ..260/247.5 3,475,429 10/1969 Woitun ..260/247.1

FOREIGN PATENTS OR APPLICATIONS 1,057,612 2/1967 United Kingdom260/247.1

OTHER PUBLICATIONS Chem. Abstr.

l-luebner 260/3068 Primary Examiner-R. Gallagher Attorney, Agent, orFirm-Hammond & Littell [57] ABSTRACT Compounds of the formula l 1 T t IR3 I S)\]/ 2 wherein:

R and R which may be identical to or different from each other, are eacha. heterocyclic amino selected from the group consisting of piperazino,N'-benzyl-piperazino, N-lower alkyl piperazino, N-(hydroxyl0wer alkyl)-piperazino, l ,4-diazacyclo-heptano, morpholino, thiomorpholino, 1-oxidothiomorpholino, l l -dioxide-thiomorpholino,hexahydro-1,4-thiazepino and l-oxido-hexahydro-l ,4-thioazepino, whereeach of these heterocycles may optionally have one or two lower alkylsubstituents attached to ring carbon atoms; or b. acyclic amino selectedfrom the group consisting of di-lower alkanol-amino,N-(methylmercapto-ethyl)-methylamino andN-(methylsulfinyl-ethyl)-methylamino; and R and R which may be identicalto or different from each other, are each hydrogen, halogen, loweralkyl, phenyl or nitro, and their non-toxic, pharmacologicallyacceptable acid addition salts; the compounds as well as their salts areuseful as inhibitors of thrombocyte aggregation and adhesiveness, andthose were R and/or R is l-oxide-thiomorpholino are also useful ashypotensives.

9 Claims, N0 Drawings 1 2,4-DIAMINO-SUBSTITUTED THIENO(3,2-D)PYRIMIDINESAND SALTS THEREOF This invention relates to novel 2,4-diaminosubstitutedthieno[3,2 -d]pyrimidines and acid addition salts thereof, as well as tomethods of preparing these compounds. I

More particularly, the present invention relates to a novel class ofthieno[3,2-d]pyrimidines represented by the formula A R S wherein: R,and R which may be identical to or different from each other, are eacha. heterocyclic amino selected from the group consisting of piperazino,N'-benzyl-piperazino, N- lower alkyl-piperazino,N'-(hydroxy-loweralkyl)-piperazino, 1,4-diazacyclo-heptano, morpholino,thiomorpholino," loxidothiomorpholino, l,l-dioxidothiomorpholino,hexahydro-l,4-thiazepino and l-oxido-hexahydrol ,4-thiazepino, whereeach of these heterocycles may optionally have one or two lower alkylsubstituents attached to ring carbon atoms; or b. acyclic amino selectedfrom the groupconsisting of di-lower alkanol-amino,N-(methylmercaptoethyl)-methylamino andN-(methylsulfinylethyl)-methylamino; and R and R which may be identicalto or different from each other, are each hydrogen, halogen, loweralkyl, phenyl or nitro, and their non-toxic, pharmacologicallyacceptable acid addition salts.

The compounds embraced by formula I may be prepared by reacting athieno[3,2-d]pyrimidine of the formula wherein R, and R have the samemeanings as in formula I.

Dependinguponthe reactivity of the exchangeable substituent Z, or Z thereaction is carried out at a temperature between 0 and 250C, optionallyin the presence of. an acid binding agent, and advantageously in asolvent medium, such as dioxane, glycol dimethyl ether,dimethylsulfoxide, ethanol or a sufficient excess of the amine reactantof the formula III (a) or (b) over and above the stoichiometricallyrequired amount.

More particularly, if Z is halogen or lower alkyl-, aryl oraralkyl-substituted sulfinyl or sulfonyl, the reaction is preferablyperformed at a temperature between 100 and 150C; on the other hand, if Zis mercapto or lower alkyl-, arylor aralkyl-substituted mercapto, thereaction is preferably carried out in a pressure vessel at a temperatureof 150 to 200C.

If Z is halogen, the reaction is preferably performed at a temperaturebetween 0 and 40C, but if Z is mercapto or lower; alkyl-, aryloraralkyl-substituted mercapto, sulfinyl orsulfonyl, it is preferablyperformed at a temperature between 100 and-200C.

In order to prepare acompound of the-formula I wherein R and R areidentical, the starting compound may also be one of the formula IIwherein Z and Z are both exchangeable substituents of the type definedin connection with formula II, and the reaction then proceeds stepwise.For example, if the starting compound is a 2,4-dichloro-substitutedthieno[3,2-d]pyrimidine .of the formula II, the chlorine atom in the4-position is exchanged for the amino-substituent at a temperaturebetween 0 and-40C, while the chlorine atom in the 2- alkylposition isnot exchanged until more elevated temperatures are applied.

For the preparation of a compound of the formula I wherein R and/or R isan N-unsubstituted piperazino or l,4-diazacycloheptano group, it is offurther advantage if the imino group in the starting compound of theformula II and/or one imino group in the piperazine or1,4-diazacycloheptane reactant is protected during the reaction by aconventional acyl protective group, such as carbethoxy, formyl,acetyl-or benzoyl. This protective group can subsequently be split offagain, for instance by hydrolysis in the presence of an acid or a baseat temperatures up to the boiling point of the solvent medium. In thecase of S-oxide compounds, however, the removal of the acyl protectivegroup is preferably effected by hydrolysis in the presence of a base,such as potassium hydroxide.

The starting compounds of the formula II required for .this method maybe prepared by processes described in the literature; see, for example,German Offenlegungsschrift No..,l,470,356 and U.S. Pat. No. 3,475,429.

Thus, by reacting a 2,4-dichloro-thieno[3,2- d]pyrimidine with an amineat relatively low temperatures, such as between 0 and 40C, acorresponding 2-chloro-4-amino-thieno [3,2-d1pyrimidine of the formulaII is obtained.

MIld hydrolysis of a 2,4-dichloro-thieno[3,2- d]pyrimidine with onemolar equivalent of an alkali metal hydroxide at lower temperaturesyields the corresponding 2-chloro-4-hydroxy-thieno[ 3 ,2-d]pyrimidine,

which is subsequently reacted at more elevated temperatures with anamine to yield the corresponding 2- --'amino4-hydroxy-thieno[3,2-d]pyrimidine which, in

turn, is coverted into the corresponding 2-amino-4-halo-thieno[3,2-d1pyrimidine of the formula II by conventional methods.

A 2- or 4-halo-substituted thieno[3,2-d]pyrimidine of the formula [I maybe converted with a corresponding mercapto or hydroxy compound in thepresence of a strong base into the analogous 2- or 4-mercaptoorhydroxy-substituted thieno[3,2-d1pyrimidine of the water. The aqueousphase was extracted with chloroform, the organic extract solution wasdried with anhydrous sodium carbonate, the chloroform was evaporated invacuo, and the crystalline residue was recrystallized twice fromethanol/dioxane in the presence of activated charcoal, yielding 40 gm(50% of theory) of 7-bromo-2 ,4-dichlo ro-thieno[ 3 ,2-d pyrimidine,

m.p. formula II. A 2- or 4-mercapto-substituted thieno[3,2- l77.5178.5C.

Analysis: C H Br Cl N S; mol.wt. 284.0 Calculated: C-25.40%; H-0.36%;Br-28.l8%; N-9.88%; S-l 1.30% Found: C-25.80%; H-O.52%; Br-27.90%;N-9.86%; S-l 1.35%

d]pyrimidine thus obtained may then be converted by oxidation into theanalogous sulfinylor sulfonylsubstituted thieno[3,2-d]pyrimidine of theformula II.

The starting compounds of the formula 11 wherein R and/or R are halogenor nitro may be prepared by halogenation or nitration, respectively, of2,4-dihydroxy- 20 thieno[3,2-d1pyrimidine, conversion of the reactionproduction into the corresponding 2,4-diahalothieno[3,2-d1pyrimidine,followed by reaction of the latter with an amine at relatively lowtemperatures, such as between and 40C.

The compounds embraced by formula I are organic bases and therefore formacid addition salts with inorganic or organic acids. Examples ofnon-toxic, pharmacologically acceptable acid addition salts are thoseformed with hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, lactic acid, citric acid, tartaric acid, maleic acid,8-chlorotheophylline or the like.

The following examples further illustrate the present invention and willenable others skilled in the art to understand it more completely. Itshould be understood, however, that the invention is not limited solelyto the particular examples given below.

PREPARATION OF STARTING COMPOUNDS OF THE FORMULA II:

EXAMPLE A 7-Bromo-2,4-dichloro-thieno[ 3,2-d]pyrimidine 90 gm (0.54 mol)of 2,4-dihydroxy-thieno[3,2- d]pyrimidine (prepared from methyl3-aminothiophene-2-carboxylate and urea) were suspended in 2.5 liters ofglacial acetic acid, the suspension was heated to 80C, and then, whilestirring, 275 gm (1.72 mols) of bromine were added dropwise to the hotsuspension. The resulting mixture was stirred for 2 hours more at 80C,subsequently concentrated to 500 ml in vacuo and then poured into about2 liters of water. The crystalline 7-bromo-2,4-dihydroxy-thieno[ 3 ,2-d]pyrimidine precipitated thereby was collected by vacuum filtration anddried at 100C in vacuo. Yield of raw product: 85 gm.

70 gm (0.282 mol) of raw 7-bromo-2,4-dihydroxythieno[3,2'd]pyrimidinewere introduced into a mixture consisting of 600 ml of phosphorusoxychloride and 80 ml of pyridine; the temperature of the mixture roseto about 60C and it turned dark while substantially all of thethienopyrimidine went into solution. In order to cause the reaction togo to completion, the mixture was refluxed for 2 hours. Thereafter, theexcess unreacted phosphorus oxychloride was distilled off in vacuo, andthe residue was carefully stirred into ice EXAMPLE B 2,4,6- and2,4,7-trichloro-thieno[3,2-d]pyrimidine 200 gm (1.19 mol) of2,4-dihydroxy-thieno[3,2- d]pyrimidine were suspended in 3 liters ofglacial acetic acid, and the suspension was heated to reflux. 120 gm(1.7 mols) of chlorine were introduced over a period of hours into therefluxing suspension, whereby the thienopyrimidine went into solution,and

5 the mixture turned brown. Thereafter, the reactiondroxy-thieno[3,2-d]pyrimidine, was collected by vacuum filtration,washed with acetone and dried at C in vacuo. Yield of raw product: 160gm.

The raw isomeric mixture thus obtained was suspended in 1.4 liters ofphosphorus oxychloride, and the suspension was refluxed for 8 hours,whereby a clear, dark solution was formed. The reaction solution wasconcentrated by evaporation in vacuo to about 400 ml and then carefullystirred into 2 liters of ice water. The aqueous phase was extracted fivetimes with 500 m1 of chloroform each, and the combined chloroformextracts were de-colorized by treatment with activated charcoal, driedover sodium sulfate and evaporated to dryness. The residue gm) wasseparated into its components by column chromatography on silicagel(particle size 0.05-0.2 mm; flow agent: Hexane/methylene chloride 1:3).The eluate contained first a small amount of2,4,6,7-tetrachloro-thieno[3,2- d]pyrimidine, then a fraction of2,4,6-trichlorothieno[3,2-d]pyrimidine and finally a fraction of 2,4,7-trichloro-thieno[3,2-d]pyrimidine. The uniform fractions were evaporatedto dryness, and the residue was recrystallized, yielding:

a. 1.6 gm of 2,4,6,7-tetrachloro-thieno[3,2- d]pyrimidine, m.p. ll8l20C.

Analysis: C CL,N S; mol.wt. 273.94 Calculate: C-26.32%; H-0.00%;N-lO.22% Found: 026.25%; H-0.17%; N-10.27%

b. 70 gm (24.6% of theory) of 2,4,6-trichlorothieno[3,2-d1pyrimidine,mp. 144C (from ethanol).

Analysis: C H Cl N S; mol.wt. 239.5 3 A l i C6H1C|2N3O2S; mol.wt. 250.08Calculated: 030.50%; l-1-0.42%;N-11.72%;S-13.40% C 1 1 t I 3.2 17- .0416 Found: 029.55%; 110.32%; N-12.14%; S-l3.61% g if 'j e 2138. 2? b 8322E 72 223? c. 40 gm (14.1% of theory) of2,4,7-trichlorothieno[3,2-d]pyrimidine, m.p. 177.5178.5C (form EXAMPLEDisopropanol).

10 2-Chloro-4-morphol1no-6-n1tro-thieno[ 3,2-

d]pyrimidine 2,4-Dichloro-6-nitroand 2,4-dichloro-7-nitro-thieno[ 3,2-d]pyrimidine 142.5 gm (0.85 mol) of 2,4-dihydroxy-thieno[3,2d]

A mixture consisting of 2.5 gm (0.01 mol) of 2,4-dichloro-6-nitro-thieno[3,2-d]pyrimidine, 2.6 gm (0.03 mol). ofmorpholine and 100 ml of ethanol was stirred for 5 hours at roomtemperature and thereafter admixed with double volume of water. Theyellow crystalline precipitate formed thereby was colled by vacuumfiltration, washed with water and recrystallized from ethanol/dioxane,yielding 2.5 gm (83.0% of theory) of 2-chloro-4-morpholino-thieno[3,2-d]pyrimidine, mp. 272C.

Analysis: C H ClN O S; mol.wt. 300.74 Calculated: 039.95%; H'3.02%; CH1.78%; N-l8.63%; S-10.66% Found: C-40.05%; H-2.94%; CH 1.95%; N-18.47%;S-10.42%

The raw isomeric mixture was added to a mixture of o 500 ml ofphosphorus oxychloride and 75 ml of pyridine, and the mixture wasrefluxed until a clear, reddish brown solution hand formed, whichrequired about four hours. Thereafter, the excess unreacted phosphorusoxychloride was evaporated in vacuo, and the residue was carefullypoured over ice. The light brown precipitate formed thereby wascollected by vacuum filtration, washed with water until neutral, driedin vacuo and separated into its components by column chromatography onsilicagel (particle size: 0.2 0.5 mm; flow agent: Hexane/ethyl acetate=5:l The eluate yielded two successive uniform fractions, each of whichwas evaporated to dryness. Recrystallization of the residues yielded 7a. 21 gm (16% of theory) of 2,4-dichloro-6-nitrothieno[3,2-d]pyrimidine, mp. 171C (from isopropanol).

Preparation of end products of the formula 1:

EXAMPLE 1 7-Bromo-2-piperazino-4-(thiomorpholino-1 '-oxidethieno[3,2-d]pyrimidine and its hydrochloride 6 gm (0.016 mol) of7-bromo-2-chloro-4- (thiomorpholino-l '-oxide)-thieno[3 .2-d]pyridine(mp. 215C) were stirred into 10 gm of molten anhydrous piperazine at C,and the mixture was maintained at 140C for 15 minutes more. Thereafter,the reaction mixture was allowed to cool and was then poured into 7water. :The resulting aqueous mixture was extracted which had a meltingpoint of 229C.

Camus;

Analysis: mol.wt. 250.0s Calculated: 028.80%; 110.40%; C1-28.37%;N-16.80%; S-12.82%

Found: 029.00%; H-0.49%;

Cl-28.70%; N-l6.57%; S-i2.70%

0 Analysis:

C l-l Br N OS mol.wt. 416.37 Calculated: 040.40%; H-4.36%; Br-19.207S-15.40% Found: 040.45%; H-4.34%', Br-19.23%; S-15.21%

The free base thus obtained was dissolved in a sufficient amount ofethanol, the resulting solution was NOB acidified with ethanolichydrochloric acid, and ether 1 was added to the acid solution. Theprecipitate formed thereby was collected and recrystallized from iso- 5propanol/water, yielding the hydrochloride monohy drate of the base,m.p. 256-258C.

Analysis: C H Br N,,OS2 I HCl H2O, mol.wt. 470.86 Calculated: 035.71%;H-4.50%; N-l4.87%; Cl-7v53%; Brl6.97% Found: 036.02%; H-4.32%; N-14.85%;Cl-7 .55%; Br-l7.20%

' EXAMPLE 2 I i v I was prepared from 7-bromo-2-chloro-4-thiomor- I v o0 Using a procedure analogous to that described in E 223 ;113:222? m-P-189 C) am le 1, 7-bromo-2- i erazino-4-mor holino-' thignow yrimidine mg ofpthe Its hydrochloride monohydrate had a melting point mula p of296297C (from isopropanol/water).

EXAMPLE 5 Using a procedure analogous to that described inExl-dioxide)-thieno[3,2-d]pyrimidine of the formula Br I I g A\ i amplel, 7-bromo-2-piperazino-4-( thiomorpholino-l 3- v N was prepared from7-bromo-2-chloro-4-morpholino- C thieno[3,2-d] pyrimidine (mp 212C) andpiperazine. S:

M$ EXAMPLE 3 Using a procedure analogous to that described in EX- 40 P Rfrom I -f ample 1, 7-bromo-2-diethanolamino-4- (thIOIPOFRhOImO'I f(thiornorpholino-l '-oxide)-thieno[3,2-d]pyrimidine, dlpyrlmldme "l-P298 p p r 0 mp (from dioxane), of the formula lts hydrochloride had amelting point of 299-30l C (from ethanol/water).

i 45 EXAMPLE 6 7 Br (1 H OH Using a procedure analogous to thatdescribed in Ex- N ample l, 7-chloro-2-piperazino-4-morpholinol l OHthieno [3,2-d]pyrimidine of the formula sO N i O was prepared from7-bromo-2-chloro-4- 0 was prepared from 2,7-dichloro-4-morpholinog g:)2:; 823 213255 thieno[3,2-d]pyrimidine (m.p. l86l87C) and piperazine.

lts dihydrochloride monohydrate had a melting point of 256C (decomp.;from ethanol/water).

EXAMPLE 4 i Using a procedure analogous to that described in Ex- EXAMPLE7 mpl -P P P fl Using a procedure analogous to that described in Ex- ]Pyof the formula ample l, 7-chloro-2-piperazino-4-(thiomorpholino-l 9oxide)-thieno[3,2-d]pyrimidine, m.p. 245-246.5C C2HL OH (from xylene),of the formula C2HL| OH was prepared from2,7-dichloro-4-(thiomorpholino-1 oxide)-thieno[3,2-d]pyrimidine (m.p.244245C) and diethanolamine.

was prepared from 2,7-dichloro-4-(thiomorpholino-l l5oxide)-thieno[3,2-d]pyrimidine (m.p. 244245C) and piperazine.

EXAMPLE 8 Using a procedure analogous to that described in Example 1,7-chloro-2-piperazino-4-thiomorpholinothieno[3,2-d]pyrimidine of theformula was prepared from2,7-dichloro-4-thiomorpholinothieno[3,2-d]pyrimidine (m.p. 179C) andpiperazine.

Its hydrochloride dihydrate had a melting point of 288C (decomp; fromethanol/water).

EXAMPLE 9 Using a procedure analogous to that described in Example7-chloro-2-piperazino-4-(thiomorpholinol',1-dioxide)-thieno[3,2-d]pyrimidineof the formula o ll was prepared from2,7-dichloro-4-(thiomorpholinol',1'-dioxide)-thieno[3,2-d]pyrimidine(m.p. 3l23l3C) and piperazine.

Its hydrochloride trihydrate had a melting point of 281C (decomp.; fromethanol/water). 5O

EXAMPLE 10 Using a procedure analogous to that described in Example l,7-chloro-2-diethanolamino-4- (thiomorpholino-l -oxide)-thieno[3,2-d]pyrimidine, m.p. l79-l80C, of the formula EXAMPLE 1 1Using a procedure analogous to that described in Example 1,6,7-dichloro-2-piperazino-4-(thiomorpholinol-oxide)-thieno[3,2-d]pyrimidine,m.p. 230-232C (from isopropanol), of the formula EXAMPLE 12 Using aprocedure analogous to that described in Example7-chloro-2-(N-methyl-piperazino)-4- (thiomorpholino-l -oxide)-thieno[3,2-d]pyrimidine, mp. C (from isopropanol), of the formula was preparedfrom 2,7-dichloro-4-(thiomorpholino-1'- oxide)-thieno[3,2-d]pyrimidine(m.p. 244245C) and N-methyl-piperazine.

EXAMPLE l3 4-Morpholino-7 -nitro-2-piperazino-thieno[ 3 ,2- d pyrimidineA solution of 2.26 gm (0.0075 mol) of 2-chloro-4-morpholino-7-nitro-thieno[ 3 ,2-d]pyrimidine (m .p. 208C) and 6.5 gm(0.075 mol) of anhydrous piperazine in 50 ml of dioxane was refluxed for30 minutes. Thereafter, the dark orange reaction mixture was allowed tocool, taken up in methylene chloride, washed three times with water,dried over sodium sulfate and filtered through activated charcoal. Thefiltrate was evaporated, and the residual crystalline substance wasrecrystallized from isopropanol, yielding 2.0 gm (76% of theory) of thecompound of the formula which had a melting point of 202205C.

Analysis: 1 C H N O S; mol.wt. 350.41 Calculated: 048.00%; H-5.17%;N-24.00%; S-9.14% Found: C-47.90%; H-5.14%; N-23.70%; S-9.22%

EXAMPLE 14 Using a procedure analogous to that described in Example 13,2-piperazino-4-thiomorpholino-7-nitrothieno[3,2-d]pyrimidine, m.p. ofits hydrochloride 282C (from ethanol/water), was prepared from 2-chloro-4-thiomorpholino-7-nitro-thieno[3,2- d]pyrimidine (m.p. 217C) andpiperazine; the reaction time was 3 hours.

EXAMPLE 15 Using a procedure analogous to that described in Example 13,2-piperazino-4-(thiomorpholino-1 '-oxide)-7-nitro-thieno[3,2-d]pyrimidine, m.p. of its hydrochloride semihydrate245C (decomp.), was prepared from i2-chloro-4-(thiomorpholino-1-oxide)-7-nitrothieno[3,2-d]pyrimidine (m.p.216218C) and piperazine; the reaction time was 3 hours.

EXAMPLE 16 Using a procedure analogous to that described in Example 13,2-piperazino-4-(thiomorpholino-l ,1dioxide)-7-nitro-thieno[3,2-d]pyrimidine, m.p. of its hydrochloridemonohydrate 330C (from ethanol/- water), was prepared from2-chloro-4-(thiomopholino- 1,1-dioxide)-7-nitro-thieno[3,2-d]pyrimidine(m.p. 267C) and piperazine; the reaction time was 2 hours.

EXAMPLE 17 Using a procedure analogous to that described in Example 13,2-piperazino-4-morpholino-6-nitrothieno[3,2-d]pyrimidine, m.p. 196C(decomp.), was prepared from2-chloro-4-morpholino-6-nitrothieno[3,2-d]pyrimidine (m.p. 272C) andpiperazine; the reaction temperature was 70C and the reaction time was30 minutes.

EXAMPLE 18 EXAMPLE 19 Using a procedure analogous to that described inExample 13, 2-piperazino-4-(thiomorpholino-l -oxide6-nitro-thieno[3,2-d]pyrimidine, m.p. of its hydrochloride monohydrate330C (from ethanol/water), was prepared from2-chloro-4-(thiomorpholino-1'-oxide)- 6-nitro-thieno[3,2-d]pyrimidine(m.p. 293C, decomp.) and piperazine; the reaction temperature was C andthe reaction time 1 hour.

EXAMPLE 20 Using a procedure analogous to that described in Example 13,2-piperazino-4-(thiomorpholino-1 ,1 dioxide)-6 -nitro-thieno[ 3 ,2-dpyrimidine, m .p. 300C, was prepared from 2-chloro-4-(thiomorpholino-1',l '-dioxide)-6-nitro-thieno[ 3,2- d]pyrimidine (m.p.269C) and piperazine; the reaction temperature was 60C and the reactiontime 30 minutes.

EXAMPLE 21 Using a procedure analogous to that described in Example 132-piperazino-4-morpholino-6-chlorothieno[3,2-d]pyrimidine, m.p. of itsdihydrochloride semihydrate 195C (decomp. from ethanol/water), wasprepared from 2,6-dichloro- 4-morpholino-thieno[3,2-d]pyrimidine (m.p.169C) and piperazine; the reaction mixture was refluxed for 3 hours.

EXAMPLE 22 Using a procedure analogous to that described in Example 13,2-piperazino-4thiomorpholino-6-chlorothieno[3,2-d1pyrimidine, m.p. ofits dihydrochloride semihydrate 265C (decomp. from ethanol/water), wasprepared from 2,6-dichloro-4-thiomorpholinothieno[3,2-d1pyrimidine (m.p.165C) and piperazine; the reaction mixture was refluxed for 3 hours.

EXAMPLE 23 Using a procedure analogous to that described in Example 13,2-piperazino-4-thiomorpholino-1 ,1

dioxide)-6-chloro-thieno[3,2-d]pyrimidine, m.p. of its hydrochloridesemihydrate 280C (decomp.), was prepared from2,6-dichloro-4-(thiomorpholino-1 ',1 '-dioxide)-thieno[3,2-d]pyrimidine(m.p. 237238C) and piperazine; the reaction mixture was refluxed for 2hours.

EXAMPLE 24 Using a procedure analogous to that described in Example 132-piperazino-4-(thiomorpholino-1-oxide)-6-chloro-thieno[3,2-d]pyrimidine, m.p. of its dihydrochloridemonohydrate 208C (decomp.), was prepared from 2,6-dich1oro-4-(thiomorpholino-1 -oxide)- thieno[3,2-d]pyrimidine (m.p. 263C) andpiperazine; the reaction mixture was refluxed for 3 hours.

EXAMPLE 25 2-Piperazino-4-( thiomorpholino- 1 '-oxide)-thieno[ 3 ,2-d]pyrimidine a. A mixture consisting of 10 gm (0.035 mol) of 2-chloro-4-(thiomorpholino-l -oxide)-thieno[ 3 ,2- d]pyrimidine (mp. 233C)and 14 gm (0.088 mol) of N-carbethoxy-piperazine was heated for 20minutes at C, allowed to cool and then poured into ice water.

The precipitate formed thereby was collected by vacuum filtration,washed with water, dried and recrystallized from toluene, yielding 10.2gm (73% of theory) of2-(N'carbethoxy-piperazino)-4-(thiomorpholinol'-oxide)-thieno[3,2-d1pyrimidine,m.p. 197l98C.

Analysis: C, l-l ,-,N O S mol.wt. 409.54 Calculated: 649.97%; 116.65%;N-l7. S-l5.63% Found: C-50.25%; H-5.60%; N-l7.05%; S-l5.84%

b. A mixture consisting of 10.2 gm (0.025 mol) of the end product of(a),12 gm (0.214 mol) of potassium hydroxide and 250 ml of isopropanol wasrefluxed for .10 hours. Thereafter, the isopropanol was substantiallyevaporated in vacuo, the residue was admixed with water, and the aqueousmixture was extracted with methylene chloride. The organic extractsolution was washed with water, dried over sodium sulfate, and themethylene chloride was evaporated in vacuo. The residue wasrecrystallized from isopropanol, yielding 6.5 gm (78% of theory) of thecompound of the formula which had a melting point of l66l68C.

Analysis: C H N OS- mol.wt. 337.46

Calculated: 049.80%; H-5.78%; N-20.74%

Found: C-49.60%; H-5.9l%; N-20.70%

EXAMPLE 26 Using a procedure analogous to that described in Example 252-(thiomorpholino-l -oxide)-4-piperazine-6-methyl-thieno[3,2-dlpyrimidine, mp. 248C (from ethanol/dioxane) of theformula was prepared from.2-chloro-4-(N'-carbethoxypiperazino)-6-methyl-thieno[3,2-d]pyrimidine(mp. 167C) and thiomorpholine-l-oxide, followed by hydrolysis of theintermediate 2-(thiomorpholino-l'-oxide)-4-(N'-carbethoxy-piperazino)-6-methylthieno[3,2-d]pyrimidine (mp.230C).

EXAMPLE 27 Using a procedure analogous to that described in Example 252-(thiomorpholino-l '-oxide)-4-piperazinothieno[3,2-d]pyrimidine, m.p.2l22l3C (from isopropanol) was prepared from 2-chloro-4-(N-carbethoxy-piperazino )-thieno[3,2-d]pyrimidine (m.p. l45146C) andthiomorpholine-l-oxide, followed by hydrolysis of the intermediate2-(thiomorpholino-l'- oxide )-4-(N'-carbethoxy-piperazino)-thieno[ 3 ,2-d]pyrimidine (mp. l96-197C).

EXAMPLE 28 Using a procedure analogous to that described in Example 25,2-thiomorpholino-4-piperazino-thieno[3,2- d]pyrimidine, m.p. of itsdihydrochloride monohydrate 294C (decomp. from isopropanol/water), wasprepared from 2- chloro-4-(N'-carbethoxy-piperazino)-thieno[3,2-d]pyrimidine (m.p. l45l46C) and thiomorpholine, followed byhydrolysis of the intermediate2-thiomorpholine-4-(N'-carbethoxy-piperazino)- thieno[3,2-d]pyrimidine(m.p. l54155C).

EXAMPLE 29 Using a procedure analogous to thatdescribed in Example 25,2-(thiomorpholino-l l'-dioxide) -4- piperazino-thieno[3,2-dlpyrimidine,m.p. of its dihydrochloride 245 C (decomp.; from isopropanol/water), ofthe formula was prepared from2-chlor0-4-(N'-carbethoxypiperazino)-thieno[ 3 ,2-d]pyrimidine (m.p.l45-146C) and thiomorpholine-l,l-dioxide, followed by hydrolysis of theintermediate 2- (thiomorpholino- 11'-dioxide)-4-(N'-carbethoxypiperazino )-thieno[ 3 ,2-d ]pyrimidine (m.p.

EXAMPLE 30 EXAMPLE 32 Using a procedure analogous to that described inExample 25, 2-[N-(B-methylmercapto-ethyl)-methylamino]-4-piperazino-6-methyl-thieno[3,2- d]pyrimidine, 122C (fromisopropanol) of the formula CH2-CH2-SCH3 7 v was prepared from2-chloro-4-(N-carbethoxypiperazino)-6-methyl-thieno[3,2-d]pyrimidine(m.p. 167C) and N-( B-methyl-mercapto-ethyl)- methylamine, followed byhydrolysis of the intermediate 2-[N-( B-methylmercapto-ethyl)-methylamino[-4- (N,'-carbethoxypiperazino )-6-methyl-thieno 3 ,2-d]pyrimidine (m.p. l05107C).

EXAMPLE 33 Using a procedure analogous to that described in Example 25,2-[N-(B-methylsulfinyl-ethyl)- methylamino]-4-piperazino--methyl-thieno[3,2- d]pyrimidine, m.p. of its dihydrochloride 232C (decomp.; fromisopropanol), of the formula was 7 prepared vpiperazino)-6-methyl-thieno[3, 2-d]pyrimidin e 167C) andN-('B-methyl-sulfinyl-ethyl)-methylamine,

followed by hydrolysis ofthe intermediate 2-[N#(B-methylsulfinyl-ethyl)-methylamino[-4-(N'-carbethoxypiperazino)-6-methyl-thieno[-3,2-d]pyrimidine(m.p.

EXAMPLE 34 Using avprocedure analogous to that described in Example 25,2-thiomorpholino-4-piperazino-6-ch1orothien0[3,2-d]pyrimidine, m.p. 194C(from .iso-

propanol/gasoline), was prepared from 2,6-dich10ro-4- (N-carbethoxy-piperazino )-.thieno 3 ,2-d pyrimidine (m.p. 178C) andthiomorpholine foll0w'ed'byhydro- 1 lysis of the, intermediate2-thiom0rpholino -"4-(N- carbethoXy-piperaziiio)-6 chloro-thien0[3,2-d]pyrimidine (m. p. 157C). I: V

Y EXAMPLE 35 Using a procedure analogous to that described'in Example25, thieno[3,2-d]pyrimidine, m.p. 178179C, was prepared from2,6-dichloro-4-(N'-carbethoxypiperazino)-thieno[3,2-d]pyrimidine (m.p.178C) and morpholine, followed by hydrolysis of the intermediate2-morpholino-4-(N-carbethoxy-piperazino)-6-chlorothieno[3,2-d]pyrimidine (m.p. 157C).

EXAMPLE 36 Using a procedure analogous to that described in Example 25,2-(thiomorpholino-1'-0xide)-4-piperazino- 6-chl0ro-thieno[3,2-d]pyrimidine, m.p. 260 C (from ethanol/dioxane), was prepared from2,6-dichloro-4- (N'-carbethoxy-piperazino)-thieno[3,2-d]pyrimidine (m.p.178C) and thiomorpholine-l-oxide, followed by hydrolysis of theintermediate 2-thiomorph0lino-l'-oxide)-4-N-carbethoXy-piperazino)-6-chlor0- thien0[3,2-d]pyrimidine(m.p. 242C).

EXAMPLE 37 Using a procedure analogous to that described in Example I25, 2-(thiomorpholine-l l'- dioxide)-4- piperazino-6-chloro-thieno[ 3,2-d pyrimidine m .p. 255257C, was prepared from 2,6-dichl0ro-4-(N-carbethoXy-piperazino thieno[3,2-d]pyrimidine (m.p. 178C) andthiomorpholine-l,l-dioxide, followed by hydrolysis of the intermediate2-(thiom0rpholino-l', 1-dioxide)-4-(N'-carbethoXy-piperazino)-6-chlorothieno[3,2-d]pyrimidine(m.p. 248250C).

EXAMPLE 38 Using a procedure analogous to that described in Example 25,2-morpho1ino-4-piperazino-7'chlor0- thieno[3,2-d]pyrimidine, m.p.12l124C (from ligroin), was prepared from 2,7-dichloro-4-(N'-carbethoXy-piperazino)-thieno[3,2-d]pyrimidine (m.p. 174-175C) andmorpholine, followed by hydrolysis of the intermediate2-morpholino-4-(N'-carbethoxypiperazino)-7-chloro-thieno[3,2-d]pyrimidine(m.p. 193C); 7

EXAMPLE 39 Using a procedure analogous to that described in Ex-2-morpholino 4 piperazino-6-chloro- 17 ample 25,2-thiomorpholino-4-piperazino-7-chlorothieno[3,2-d1pyrimidine, m.p.ll.5l52.5C, was prepared from 2 ,7-dichloro-4-( N '-carbethoxypiperazino)-thieno[3,2-d]pyrimidine (m.p. l74l75C) andthiomorpholine, followed by hydroly- 5 sis of the intermediate2-thiomorpholino-4-(N'- carbethoxy-piperazino )-7-chloro-thieno[ 3 ,2-d]pyrimidine (m.p. l71.5-l72.5C).

EXAMPLE 40 Using a procedure analogous to that described in Example 25,Z-(thiomorpholino-l'-oxide)-4-piperazino-7-chloro-thieno[3,2-d]pyrimidine, m.p. 237238C (from toluene), wasprepared from 2,7-dichloro-4-(N-carbethoxy-piperazino)-thieno[3,2-d]pyrimidine (m.p. 174l75C) andthiomorpholine-l-oxide, followed by hydrolysis of the intermediate2-(thiomorpholino-l oxide )-4-N -carbethoxy-piperazino)-7-chlorothieno[3,2-d]pyrimidine (m.p. l97-l99C).

EXAMPLE 41 Using a procedure analogous to that described in Example 25,2-(thiomorpholino-l l'-dioxide)-4- piperazino-7-chloro-thieno[ 3,2-d]pyrimidine, mp. 231C (from ethanol/dioxane), was prepared from 2,7-dichloro-4-(N'-carbethoxy-piperazino)-thieno[3,2- d]pyrimidine (m.p.l74-l75C) and thiomorpholinel,l-dioxide, followed by hydrolysis of theintermediate 2(thiomorpholino-l l '-dioxide)-4-(N'-carbethoxypiperazino)-7-chloro-thieno[3,2-d]pyrimidine (m.p. 232C).

EXAMPLE 42 Using a procedure analogous to that described in Example 25,2-thiomorpholino-4-piperazino-7-bromothieno[3,2-d1pyrimidine, m.p. ofits hydrochloride 314C (decomp.), of the formulathieno[3,2-d]pyrimidine, m.p. of its hydrochloride semihydrate 307C(decomp.), was prepared from 2-morpholino-4-(N'-carbethoxypiperazino)-7-bromothieno[3,2-d]pyrimidine(m.p. 216C) and morpholine, followed by hydrolysis of the intermediate2-morpholino-4-(N'-carbethoxy-piperazino)-7-bromothieno[3,2-d]pyrimidine(m.p. 192-l93C).

EXAMPLE 44 Using a procedure analogous to that described in Example 25,2-thiomorpholino-4-piperazino-7-methylthieno[3,2-d]pyrimidine, m.p. ofits dihydrochloride 3053l0C (decomp., from isopropanol/water), wasprepared from2-thiomorpholino-4-(N-carbethoxypiperazino)-7-methyl-thieno[3,2-d]pyrimidine(m.p. 117C) and thiomorpholine, followed by hydrolysis of theintermediate2-thiomorpholino-4-(N'-carbethoxypiperazino)-7-methyl-thieno[3,2-d]pyrimidine(m.p. 149C).

EXAMPLE 45 2-Piperazino-4-(thiomorpholino-ll-dioxide)-7-methyl-thieno[3,2-d]pyrimidine and its dihydrochloride 10.6gm (0.033 mol) of 2-chloro-4-(thiomorpholino- 1',l-dioxide)-7-methyl-thieno[3 ,2-d]pyrimidine (m.p. 244C) were graduallyadded to 30 gm (0.35 mol) of molten anhydrous piperazine at 140C,accompanied by stirring, and the mixture was kept at 140C for 30 minutesmore. Thereafter, the reaction mixture was allowed to cool, was thenadmixed with water, and the aqueous mixture was extracted with methylenechloride. The methylene chloride extract solution was washed with water,dried over sodium sulfate, and the solvent was removed in vacuo. Theresidue was purified by column chromatography on silicagel (particlesize: 0.2-0.5 mm; flow agent: Methanol/ethyl acetate/ammonia 20:20:1),and the uniform eluate fractions were combined and evaporated. Theresidue, 2-piperazino-4-(thiomorpholino-l',1'-dioxide)-7-methyl-thieno[3,2-d]pyrimidine,was taken up in ethanol, the resulting solution was acidified withethanolic hydrochloric acid, and the precipitate formed thereby wascollected and recrystallized from ethanol/water, yielding 12 gm (76.3%of theory of the dihydrochloride dihydrate of the formula theintermediate 2-(thiomorpholino)-4-(N'- carbethoxy-piperazino-'7-bromo-thieno[ 3 ,2-

d]pyrimidine (m.p. l77.5178C).

EXAMPLE 43 Using a procedure analogous to that described in EX- ample25, 2-morpholino-4-piperazino-7-bromowhich had a melting point beginningat 200C.

Analysis: C,5H2,N5O2S2. 2HCl 2H2O; moLwt. 476.47 Calculated: 037.80%;H-5.71%; Cl-l4,87%; N-14.69%; 543.45% Found: 037.75%; H-5.52%;Cl-14.79%; N-l4.45%; S-l3,34%

EXAMPLE 46 Using a procedure analogous to that described in Example 45,2-piperazino-4-thiomorpholino-6-methy1- thieno[3,2-d]pyrimidine, m.p. ofits dihydrochloride monohydrate beginning at 257C (from ethanol), wasprepared from 2-chloro-4-thiomorpholino-6-methylthieno[3,2-d]pyrimidine(m.p. 158160C) and piperazme.

'thiazepino)-thieno[3,2-d]pyrimidine (mp. 130C) and piperazine.

EXAMPLE 48 Using a procedure analogous to that described in Example 45,2-(1, 4-diaza-cycloheptano)-4-thiomorpholino-thieno[3,2-d]pyrimidine,m.p. of its dihydrochloride 265C (from ethanol), was prepared from 2-chloro-4-thiomorpholino-thieno[3,2-dlpyrimidine (m.p. l73-174C) and1,4-diaza-cycloheptane.

EXAMPLE 49 Using a procedure analogous to that described in Example 45,2-( l 4-diaza-cycloheptano)-4- thiomorpholino-6-methyl-thieno[ 3 ,2-dpyrimidine,

of its m.p. 1161l8C, m.p. 248250C, of the formula dihydrochloride wasmethy1-thieno-[3,2-d]pyrimidine (m.p. and 1,4-diaza-cycloheptane.

prepared from 2-chloro-4-thiomorpholino-6- EXAMPLE 50 Using a procedureanalogous to that described in Example 45,2-piperazin0-4-thiomorpholino-6-phenylthieno[3,2-d]pyrimidine, m.p. ofits dihydrochloride semihydrate 260C (decomp.; from methanol), of theformula was prepared from2-chloro-4-thiomorpholino-6-phenyl-thieno[3,2-d]pyrimidine (m.p.183184C) and piperazine.

s e s EXAMPLE 51 Using a procedure analogous to that described inExample 45, 2-piperazino-4-(2-methyl-thiomorpholino- 1-oxide)-thieno[3,2-d]pyrimidine, m.p. l24-126C (from xylene/petroleum ether),of the formula -N NH l N was prepared from 2-chloro-4-(2'-methy1-thiomorpholino-l -oxide )-thieno[ 3,2-d]pyrimidine (m.p. 229230C) andpiperazine.

EXAMPLE 52 Using a procedure analogous to that described in Example 45,2-(2', 5'-dimethyl-piperazino)-4- (thiomorpholino-l '-oxide)-thieno[3,2-d]pyrimidine, m.p. of its dihydrochloride semihydrate 300304C(decomp.; from methanol/acetone), of the formula h I I TM was preparedfrom 2-ch1oro-4-(thiomorpholino-1- oxide)-thieno[3,2-d]pyrimidine (mp.233C) and 2,5-dimethyl-piperazine.

EXAMPLE 53 Using a procedure analogous to that described in Example 45,2-( l 4'-diaza-cycloheptano)-4- (thiomorpholino-l -oxide)-thieno[3,2-d]pyrimidine, m.p. of its dihydrochloride 3 153 18C (decomp.; fromethanol/water), was prepared from 2-chloro-4- (thiomorpholino-l-oxide)1thieno[ 3,2-d]pyrimidine (mp. 233C) and 1,4-diaza-cycloheptane.

EXAMPLE 54 Using a procedure analogous to that described in Example 45,2-piperazino-4-(hexahydro-l 4' "21 thiazepino-l -ox ide)-thieno[3,2d]pyrimidine, m.p. of its dihydrochloride monohydrate268-270C (decomp.; from isopropanol/water), of the formula \N NH wasprepared from 2-chloro-4-(hexahydro-l, 4- thiazepino-l '-oxide)-thieno[3,2-d]pyrimidine (m.p. l90C) and piperazine.

EXAMPLE 55 Using a procedure analogous to that described in Example 45,2-piperazino-4-(thiomorpholino-l-oxide)- 6-methylthieno[3,2-d]pyrimidine, m.p. of its dihydrochloride dihydratebeginninng at 235C (from isopropanol/water), was prepared from2-chloro-4- (thiomorpholino-l -oxide )-6-methyl-thieno[ 3,2-d]pyrimidine (mp. 228C) and piperazine.

EXAMPLE 56 Using a procedure analogous to that described in Example 452-piperazino-4-( thiornorpholino-l '-oxide6,7-dimethyl-thieno[3,2-d]pyrimidine, m.p. of its dihydrochloridemonohydrate 270C (decomp.), of the formula was prepared from2-chloro-4-(thiomorpholino-l'-oxide)-6.7-dimethyl-thieno[3,2-d]pyr'imidine and piperazine.

EXAMPLE 57 I EXAMPLE 58 Using a'p'rocedureanalogous to that described inExample 45 2-piperazino,- 4-[N-(B-methylsulfinyl-ethyl)-methylamino]-thien o[ 3,2-d]pyrimidine, mp. 'of'its dihydrochloridedihydrate' 246C (decomp.), was prepared from2-chloro-4-[N-(B-methylsulfinyl-ethyl)-methylamino]-thieno[3,2-d]pyrimidine (mp. 169C) and piperazine.

EXAMPLE 59 Using a procedure analogous to that described in Example 45,2-piperazino-4-thiomopholino-7-methylthieno[3,2-d]pyrimidine, m.p.l26-127C (from petroleum ether 5070C), was prepared from 2-chlor0-4-thiomorpholino-7-methyl-thieno[ 3 ,2-d pyrimidine (m.p. l03-l04C) andpiperazine.

EXAMPLE 60 Using a procedure analogous to that described in Example 45,2-(thiomorpholino-l'-oxide)-4-(N'-methylpiperazino)-thieno[3,2-d]pyrimidine, m.p. l77179C,was prepared from 2-chloro-4-(N-methyl-piperazine)-thieno[3,2-d]pyrimidine (m.p. 1 l7-l 18C) andthiomorpholine-l-oxide.

EXAMPLE 61 Using a procedure analogous to that described in Example 45,2-(N'-methyl-piperazino)-4- thiomorpholino-6-rnethyl-thieno[ 3,2-dlpyrimidine, m.p. of its dihydrochloride 300-302C, was prepared from2-chloro -4-thiomorph0lino-6-methyl-thieno[3,2- d]pyrimidine' (m.p.'l58160C) and N-methylpiperazine. 1

EXAMPLE 62 2-Piperazino-4-(thiomorpholino-l ,1 '-dioxide thieno[3,2-d]pyrimidine and its dihydrochloride A mixture consisting of 9.1 gm(0.03 mol) of, 2- chloro-4-(thiomorpholino-l ,l '-dioxide )-thieno[ 3,2-d]pyrimidine (mp. 264C) and 20 gm (0.232 mol) of anhydrous piperazinewas heated at to C, accompanied by stirring, until a clear molten masswas formed, which occurred after about 30 minutes. The reaction mixturewas then allowed to cool, was taken up in methylene chloride, and theresulting solution was washed severaltimes with water, dried over sodiumsulfate and evaporated in vacuo. The residue, the raw free base2-piperazino-4-(thiomorpholino-l ,l dioxide)-thieno[ 3,2-d]pyrimidine,was stirred with ethanol, the insoluble matter was filtered off, and thefiltrate was acidified with ethanolic hydrochloric acid. The precipitateformed thereby was collected by vacuum filtration and recrystallizedfrom methanol/water, yielding 11.8 gm (92.3% of theory) of thedihydrochloride of the formula I Analysis: Calculated:

2 HCl; mol.wt. 426.20 Cl-l6.62%; 845.03%

EXAMPLE 63 Using a procedure analogous to that described in Example 62,2-piperazino-4-(thiomorpholino-l'-oxide)- thieno [3,2-d]pyrimidine, mrp.l66l68C (from isopropanol), m.p. of its dihydrochloride monohydrate303305C (decomp.; from ethanol/water), was prepared from2-chloro-4-(thiomorpholino-l-oxide)- thieno[3,2-d]pyrimidine (mp. 233C)and piperazine.

EXAMPLE 64 Using a procedure analogous to that described in Example 62,2-piperazino-4-thi0morpholino-thieno[3,2- d]pyrimidine, m.p. l54l55C(from ethyl acetate/petroleum ether 5:1), was prepared from 2-chloro-4-thiomorpholino-thieno[ 3 ,2-d]pyrimidine (m.p. 173l74C) and piperazine.

EXAMPLE 9 65 Using a procedure analogous to that described in Example62, 2-piperazino-4-thiomorpholino-6,7-dimethyl-thieno[3,2-d]pyrimidine,m.p. 123-l25C (from acetone) was prepared from 2-chloro4-thiomorpholino-6,7-dimethyl-thien 0[3,2-d] pyrimidine (mp 128C) and piperazine.

EXAMPLE 66 Using a procedure analogous to that described in Example 62,2- piperazino-4-(2-methyl-thiomorpholino)- thieno [3,2-d]pyrimidine,m.p. of its dihydrochloride 263--266C (from ethanol/acetone), wasprepared from 2-chloro-4-(2-methyl-thiomorph0lino)- thieno[3,2-d]pyrimidine m.p. 157-158C) and piperazine.

EXAMPLE 67 Using a procedure analogous to that described in Example 62,2-piperazino-4-(thiomorpholino-l-oxide)-6-phenyl-thieno[3,2-d]-pyrimidine, m.p. 198200C (from isopropanol), wasprepared from 2-chloro-4- thiomorpholino-l -oxide )-6-phenyl-thieno[3,2- d]pyrimidine, m.p. 198-200C (from isopropanol), was prepared from2-chloro-4-(thiomorpholino-l'- oxide )-6-phenyl-thieno 3,2-d]pyi'imidine (m.p. l37138.5C) and piperazine.

EXAMPLE 68 Using a procedure analogous to that described in Example 62,2,4-di-(thiomorpholino-l -oxide)- thieno[3,2-d]pyrimidine, m.p. 230231C(from ethanol/ether), was prepared from 2-chloro-4- (thiomorpholino-l-oxide)-thieno[3,2-d]pyrimidine (mp. 233C) and thiomorpholino-l-oxide.

EXAMPlE 69 Using a procedure analogous to that described in Example 62,2-piperazino-4-(thiomorpholino-l"-oxide)-7-methyl-thieno[3,2-d]pyrimidine, m.p. 228-230C (from dioxan'e), m.p. ofits dihydrochloride semihydrate 243C (dec0mp.; from ethanol) wasprepared from2-chl0ro-4-(thiomorpholino-l-oxide)-7-methylthieno[3,2-d]pyrimidine (mp.239C) and piperazine.

The sulfate dihydrate, m.p. beginning at 170C (from ethanol/water), wasobtained by admixing a'methanolic solution of the free base with anequivalent amount of sulfuric acid.

The maleate, mp. 188C, was obtained in like manner with maleic acid,

EXAMPLE Using a procedure analogous to that described in Example 62,2-(N'-methyl-piperazino)-4- (thiomorpholino-l -oXide)-thien0[ 3 ,2-d]pyrimidine, m.p. of its dihydrochloride monohydrate 305C (decomp. wasprepared from 2-chloro-4- thiomorpholinol -oxide )-'thieno[ 3,2-d]pyrimidine (mp. 233C) and N-methyl-piperazine.

EXAMPLE 7 1 Using a procedure analogous to that described in Example 62,2-(N-benzyl-piperazino)-4- (thiomorpholino-l -oxide)-7-methyl-thieno[3,2- d]pyrimidine, mp. 179C (from isopropanol) of the formula wasprepared from 2-chlor0-4-(thiomorpholino-l oxide )-7-methyl-thieno[ 3,2-d pyrimidine (m .p. 239C) and N-benzylpiperazine.

EXAMPLE 72 Using a procedure analogous to that described in Example 62,2-[N-(/3-hydroxy-ethyl)-piperazino]-4- (thiomorpholino-l '-oXide)-thien0[ 3 ,2-d]pyrimidine, m.p. l20122C (from water) of the formulaamon -06 0a was prepared from 2-chloro-4-(thiomorpholino-l'-oxide)-7-methy1-thieno[3,2]pyrimidine (mp. 239C) and diethanolamine.

EXAMPLE 74 Using a procedure analogous to that described in Example 62,2-(N'-methyl-piperazino)-4- (thiomorpholino-l'-oxide)-7-methyl-thieno[3,2- d]pyrimidine, mp. 213C (fromisopropanol/water), was prepared from 2-chloro-4-(thiomorpholino-loxide)-7-methyl-thieno[3,2-d]pyrimidine (mp. 239C) andN-methyl-piperazine.

EXAMPLE 75 Using a procedure analogous to that described in Example 62,2-(N'-methyl-piperazin0)-4- (thiomorpholino-l',1-dioxide)-7-methyl-thieno[3,2- d]pyrimidine, mp. 178C (fromisopropanol), was pre- 30 pared from 2-chloro-4-(thiomorpholinol,ldioxide)-7-methyl-thieno[3,2-d]pyrimidine (mp. 244C) andN-methyl-piperazine.

EXAMPLE 76 Using a procedure analogous to that described in Example 62,2,4di-thiomorpholino-thieno[3,2- d]pyrimidine, m.p. l37l39C (fromethanol) was prepared from 2-chloro-4-thiomorpholino-thieno[3,2-d]pyrimidine (m.p. l73l74C) and thiomorpholine. 40

The point of attachment of the substituent R or R when it was chlorine,bromine or nitro in the 6- or 7- position in the above compounds of theformula I, was ascertained by means of nuclear resonance spectra and inanalogy to M. Robba et al. Bull. Soc. Chim. France 1970, 3630-3636, andTetrahedron 27, 487-499 (1971).

The compounds according to the present invention, that is, thoseembraced by formula 1 and their nontoxic, pharmacologically acceptableacid addition salts, have useful pharmacodynamic properties. Moreparticularly, the compounds of the instant invention exhibit a verystrong inhibiting action upon thrombocyte aggregration and adhesiveness(platelet stickiness), as well as hypotensive activities, in-warm-blooded animals, such as mice, cats and dogs. The hypotensiveactivity is particularly pronounced in those compounds of the formula Iwhereinn R and/or R are thiomorpholine-1 -oxide.

For instance, intrevenous administration of 0.1 mgm/kg of7-chloro-2-piperazino-4-(thiomorpholinol-oxide)- thieno[3,2-d]pyrimidineto anesthetized cats produced a 25% reduction in the blood pressure overthe normal value, and the hypotensive effect lasted for more than 60minutes.

The inhibiting action upon thrombocyte aggregation was ascertained bythe method of Born and Cross, J. Physiol. 170, 387 (1964), or by themethod of K. Bred- 26 din, Schweiz. Med. Wochenschr. 95, 655-660 (1965).

The inhibiting effect upon the platelet stickiness was determined bymeans of the so-called retention test according to Morris [see E.Deutsch et al., 1. Internationales Symposium Ueber Stoffwechsel andMembranpermeabilitaet von Erythrocyten and Thrombocyten, Vienna, Austria(1969.); Georg Thieme Verlag, Stuttgart, Germany].

The hypotensive tests were performed on anesthetized cats and dogs bythe method of Eckenhoff, Amer. J. Physiol. 148, 582 (1947).

The table below shows the results obtained from the tests forthromboctye aggregation inhibition according to the method of Morris andthe method of Born and Cross for a number of representative compoundsaccording to the present invention, namely;

A 2-Piperazino-4-(thiomorpholino-l -oxide )-7- methyl-thieno[3,2-d]pyrimidine dihydrochloride,

2-piperaZino-4-(thiomorpholino-l '-oxide)- thieno[3,2-d]pyrimidinedihydrochloride,

2-piperazino-4-(thiomorpholino-1'-oxide)-6- methyl-thieno[3,2d]pyrimidine dihydrochloride,

4-piperazino-2-(thiomorpholino-l-oxide)-6- methyl-thieno[3,2-d]pyrimidine dihydrochloride,

4-piperazino-2-(thiomorpholino-l -oxide)- thieno[ 3,2-d]pyrimidinedihydrochloride,

2-piperazino-4-thiomorpholino-7-methylthieno[3,2-d]pyrimidinedihydrochloride,

2-piperazino-4-thiomorpholino-thieno[3,2- d]pyrimidine dihydrochloride,

7-bromo-2-piperazino-4-(thiomorpholino-l oxide)-thieno [3,2-d1pyrimidinedihydrochloride,

I 7-chloro-2-piperazino-4-(thiomorpholino-l'- oxide)-thieno[3,2-d1pyrimidine dihydrochloride,

J 6-chloro-2-piperazino-4-(thiomorpholino-1'- oxide)-thieno[3,2-d]pyrimidine dihydrochloride, and

K 7-bromo-4morpholino-Z-piperazino-thieno[3,2-

d]pyrimidine dihydrochloride.

1. Determination of platelet aggregation according to Morris Todetermine the inhibiting action of the test compound upon thrombocyteaggregation, 1 ml of human blood is pipetted into small test tubes, andthe test compound is added to a final concentration of 5X10 mol/- literresp. 1X10 mol/liter. The tubes are incubated for 10 minutes at 37C. 1gm of glass beads (glass beads for gas-chromatography) is added to halfof the tubes. Finally the closed tubes are attached to a vertical wheeland rotated for 1 minute. By this means good contact is obtained betweenthe glass beads and the blood. The tubes are then allowed to stand atroom temperature for another hour, after which time a satisfactorysedimentation of erythrocytes has taken place. 0.01 ml of thesupernatant plasma is removed, diluted to 1:8,000 with celloscopesolution, and the platelet count is read in the celloscope. The percentreduction in the stickiness due to the presence of the substance(compared to tubes without glass beads) is measured and the average offour to six determinations is taken.

2. Determination of platelet aggregation according to Born and Cross Theplatelet aggregation was measured in human, platelet-rich plasma takenfrom healthy donors. The rate of decline of the optical density of theplatelet suspension was measured and registered photometrically afteradenosinediphosphate (ADP) had been added. From the slope of the densitycurve the rate of the ag- 27 gregation was estimated. The opticaldensity was taken as the point on the curve where most light wastransmitted.

The smallest possible doses of ADP were chosen, but

28 Preparation The thienopyrimidine compound is intimately admixed withthe lactose and the potato starch, the mixture is uniformly moistenedwith an ethanolic 20% soj gz g gz a reversible g g ,753? A13}, lution ofthe polyvinylpyrrolidone, the moist mass is minutes with s g l p F; at Sen forced through a 1.5 mm-mesh screen, and the result- In the table 3 525 3 1 Z i cognpoun ing granulate is dried at 45C and again passedthrough and th di i n f e g i a 1.0 mm-mesh screen. The dry granulatethus obtained h m nu 0 ransbmlsslon 0 i p a e 10 is admixed with themagnesium stearate, and the comno phasma ers i f f position iscompressed into 100 mgm-tablets in a con- ?E: f i g i gfi z lfigg i p iventional tablet making machine. Each tablet contains Case a e e l z i30 mgm of the thienopyrimidine compound and is an b r 0 es oral dosageunit composition with effective thrombonum er m es m e O ,aggrega an 6cyte aggregation and stickiness inhibiting action. 0nd number theopt1cal density.

3. The acute toxicity of some of the compounds for orientation(observation time: 14 days) was deter- EXAMPLE 78 mined on mice, or theLD was calculated from the C d percentage of animals which died afterdifferent doses Gate pl S within the observation time [see J. Pharmacol.exper. The pill core composition is compounded from the Therap. 96, 99(1949)]. following ingredients:

TABLE Morris-test Born-test LD50 p.o. Commolar-concentration molarconcentration pound 5 l0' 1 10 3X105 1X10' (mouse) A 75% 26% 65/82 /28290 mg/kg B 93% 76% 100/100 100/100 472 mg/kg C 97% 83% 100/100 100/1001070 mg/kg D 87% 54% 100/100 100/100 250 mg/kg E 100% 86% 100/100 96/98F 94% 67% 55/85 48/49 G 100% 85% 96/98 72/92 450 mg/k H 93% 91% 100/100100/100 -350 mg/ kg 1 96% 91% 100/100 250 mg/kg J 92% 91% 100/100100/100 150 mg/kg K 96% 80% 100/ 100 82/92 For pharmaceutical purposesthe compounds accord- 7-Methyl-2piperazino ing to the present inventionare administered to warml q' morphol 1n o)-th1eno[3,2- blooded animalsperorally or parenterally as act1ve 1nlpy Parts gredients in customarydosage unit compositions, that z fif :8 22: is, compositions in dosageunit form consisting essenp l i l fid s tially of an inertpharmaceutical carrier and one effec- Magnesium Steam? 0 5 Parts tivedosage unit of the active ingredient, such as tablets, T0131 Partscoated pills, capsules, wafers, powders, solution, suspensions,emulsions, syrups, suppositories and the like. Preparation One effectivedosage unit of the compounds according to the present invention is from0.083 to 1.67 mgni/kg The mgredlents f ccfmpounded a manner analo bodyweight preferably (M6 to 0.84 mgm/kg body gous to that descnbed 1n thepreceding example, and weight. The daily dose rate is from 1.66 to 3.34thcomposltlon 1S Compressed 1 40 a Cores, mgm/kg body weight which aresubsequently coated with a thin shell conslst- The following examplesillustrate a few pharmaceutimg 1 a mlxtul'e of talcum and Sugar caldosage unit compositions comprising a compound Pollshed E coated Pconlalns of the present invention as an active ingredient and rep- 15mgm of pyf l P Q and IS an resent the best modes contemplated of puttingthe in- Oral dosage P9 l f f vention into practical use. The parts areparts by weight cyte aggregatlon and Stlckmess mhlbltmg unless otherwisespecified.

EXAMPLE 77 Tablets EXAMPLE 79 The tablet composition is compounded fromthe fol- Hypodermlc Solutlon o g ingredients; The solution is compoundedfrom the following in- 2-Piperazino-4- gredients: (thiomorpholinol-oxide)- 7-methy1thieno[3,2d] v 5 pyrimidine 30.0 parts Lactose 38.0parts 7-Methyl-2-piperazino-4-( 1 '-oxido-thio- Potato starch 26.0 partsmorpholino)-thieno[3,2-dlpyrimidine 10.0 parts Polyvinylpyrrolidone 5.0parts Polyethyleneglycol 600 100.0 parts Magnesium stearate 1.0 partsDistilled water q.s.ad. 2000.0 parts Total 100.0 parts by PreparationThe polyethyleneglycol and the pyridopyrimidine salt are dissolved in asufficient amount of distilled water which had previously been boiledand cooled in an atmosphere of nitrogen; the dissolution is also carriedout in an atmosphere of nitrogen. The resulting solution is diluted tothe indicated volume with additional pretreated distilled water, and theresulting solution is filled, again in an atmosphere of nitrogen, intobrown 2 cc-ampules which are then sterilized for 20 minutes at 120C andsubsequently sealed. The entire operation must be performed in diffusedlight. Each ampule contains l mgm of the thienopyrimidine compound, andthe contents thereof are an injectable dosage unit composition witheffective thrombocyte aggregation and stickiness inhibiting action.

EXAMPLE 80 Drop Solution The solution is compounded from the followingingredients:

2-Piperazino-4-morpholino-thieno The sorbic acid is dissolved in theethanol, the solution is diluted with an equal volume of distilledwater, and the thienopyrimidine compound is dissolved in the aqueousmixture (solution 1). The cane sugar is dissolved in the remainingamount of distilled water (solution 2). Solution 2, thepolyethyleneglycol and the essence of cocoa are stirred into solution 1,and the composition is filtered. The entire operation must be performedin an atmosphere of nitrogen and in diffused light. 1 ml of the filtrate(about 20 drops) contains about mgm of the thienopyrimidine compound andis an oral dosage unit composition with effective thrombocyteaggregation and stickiness inhibiting action.

Analogous results are obtained when any one of the otherthienopyrimidines embraced by formula 1 or a non-toxic acid additionsalt thereof is substituted for the particular thienopyrimidine inExamples 77 through 80. Likewise, the amount of active ingredient inthese illustrative examples may be varied to achieve the dosage unitrange set forth above, and the amounts and nature of the inertpharmaceutical carrier ingredients may be varied to meet particularrequirements.

While the present invention has been illustrated with the aid of certainspecific embodiments thereof, it will be readily apparent to othersskilled in the art that the invention is not limited to these particularembodiments, and that various changes and modifications may 30 be madewithout departing from the spirit of the invention or the scope of theappended claims.

We claim: 1. A compound of the formula wherein:

one of R and R is piperazino, N"-methylpiperazino, N'-benzyl-piperazino,N'-(B-hydroxyethyl)-piperazino, dimethyl-piperazino orl-oxidothiomorpholino, the other of R and R is l-oxido-thiomorpholino,

l l -dioxido-thiomorpholino or Z-methyll -oxidothiomorpholino, provided,however, that R and R are other than loxido-thiomorpholino and 1 l-dioxido-thiomorpholino or 2-methyl'1-oxido-thiomorpholino,respectively, at the same time,

one of R and R is hydrogen or methyl, and the other of R and R ishydrogen, methyl, chlorine, bromine or nitro, or a non-toxic,pharmacologically acceptable acid addition salt thereof.

2. A compound according to claim 1, which is 2-piperazino-4-(thiomorpholinol '-oxide )-7-methylthieno[3,2-d1pyrimidineor a non-toxic, pharmacologically acceptable acid addition salt thereof.

3. A compound according to claim 1, which is 2-piperazino-4-(thiomorpholino-l '-oxide )-thieno[ 3 ,2- d]pyrimidine or anon-toxic, pharmacologically acceptable acid addition salt thereof.

4. A compound according to claim 1, which is 2-piperazino-4-(thiomorpholinol -oxide )-6-methylthieno[3,2-d1pyrimidineor a non-toxic, pharmacologically acceptable acid addition salt thereof.

5. A compound according to claim 1, which is 4piperazino-2-(thiomorpholino-l '-oxide)-6-methylthieno[3,2-d1pyrimidineor a non-toxic, pharmacologically acceptable acid addition salt thereof.

6. A compound according to claim 1, which is 4-piperazino-2-(thiomorpholino-1 '-oxide )-thieno[ 3 ,2- d]pyrimidine or anon-toxic, pharmacologically acceptable acid addition salt thereof.

7. A compound according to claim 1, which is 7- bromo-2-piperazino-4-(thiomorpholinol '-oxide)- thieno[3,2-d1pyrimidine or a non-toxic,pharmacologically acceptable acid addition salt thereof.

8. A compound according to claim 1, which is 7-chloro-2-piperazino-4-(thiomorpholino-l -oxide)- thieno[3,2-d1pyrimidineor a non-toxic, pharmacologically acceptable acid addition salt thereof.

9. A compound according to claim 1, which is 6- chloro-2-piperazino-4-(thiomorpholinol -oxide thieno[3,2-d]pyrimidine or a non-toxic,pharmacologically acceptable acid addition salt thereof.

UNITED STATES PATENT OFFICE (569) CERTIFICATE OF CORRECTION Patent NO.Dated J 1 lnventor(s) 3;;31' iiezuli ra l 41 uUdQL ;\@cr1 ,Ji1r-L '-ChMULLLK and Job'ilb? NICAL It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

39 Lin 5, 2E -diahaloshould read -dihalo- 3 C--30.SO}5" should read060.05%

13 L? --piperazine-'-" should read -piperazinol5 0 ."metl'1;, "lami1'10[should -metnglamino] 22 J? After calcula ted please i nsert mum: 039.20; H-5.23;;-.; cuoflrzg;

F 5O "litres-Queue shouldintravenous Engned and Sealed thls twenty-firstDay Of October 1975 [SEAL] Attest:

RUTH C. MASON C. MARSHALL DANN Arresting Officer Commissioner o/Parentsand Trademarks

1. A COMPOUND OF THE FORMULA
 2. A compound according to claim 1, whichis2-piperazino-4-(thiomorpholino-1''-oxide)-7-methyl-thieno(3,2-d)pyrimidineor a non-toxic, pharmacologically acceptable acid addition salt thereof.3. A compound according to claim 1, which is2-piperazino-4-(thiomorpholino-1''-oxide)-thieno(3,2-d)pyrimidine or anon-toxic, pharmacologically acceptable acid addition salt thereof.
 4. Acompound according to claim 1, which is2-piperazino-4-(thiomorpholino-1''-oxide)-6-methyl-thieno(3,2-d)pyrimidine or a non-toxic, pharmacologically acceptable acidaddition salt thereof.
 5. A compound according to claim 1, which is4-piperazino-2-(thiomorpholino-1''-oxide)-6-methyl-thieno(3,2-d)pyrimidineor a non-toxic, pharmacologically acceptable acid addition salt thereof.6. A compound according to claim 1, which is4-piperazino-2-(thiomorpholino-1''-oxide)-thieno( 3,2-d)pyrimidine or anon-toxic, pharmacologically acceptable acid addition salt thereof.
 7. Acompound according to claim 1, which is7-bromo-2-piperazino-4-(thiomorpholino-1''-oxide)-thieno(3,2-d)pyrimidineor a non-toxic, pharmacologically acceptable acid addition salt thereof.8. A compound according to claim 1, which is7-chloro-2-piperazino-4-(thiomorpholino-1''-oxide)-thieno(3,2-d)pyrimidine or a non-toxic, pharmacologically acceptable acid additionsalt thereof.
 9. A compound according to claim 1, which is6-chloro-2-piperazino-4-(thiomorpholino-1-oxide)-thieno(3,2-d)pyrimidineor a non-toxic, pharmacologically acceptable acid addition salt thereof.